Complement Inhibition: A Novel Form of Immunotherapy for Colon Cancer

Abstract

Background Complement is a central part of both the innate and adaptive immune response and its activation has traditionally been considered part of the immunosurveillance response against cancer. Its pro-inflammatory role and its contribution to the development of many illnesses associated with inflammatory states implicate complement in carcinogenesis. Methods We evaluated the role of three protein inhibitors of complement—cobra venom factor, humanized cobra venom factor, and recombinant staphylococcus aureus superantigen-like protein 7—in the setting of a transplantable murine colon cancer model. Outcomes were evaluated by monitoring tumor growth, and flow cytometry, ELISPOT, and quantitative real-time PCR were used to determine the impact of complement inhibition on the host immune response. Results Complement inhibitors were effective at depleting complement component C3 in tumor bearing mice and this was temporally correlated with a decreased rate of tumor growth during the establishment of tumors. Treatment with cobra venom factor resulted in increased CD8+ T cells as a percentage of tumor-infiltrating cells as well as a reduced immunosuppressive environment evidenced by decreased myeloid derived suppressor cells in splenocytes of treated mice. Complement inhibition resulted in increased expression of the chemoattractive cytokines CCL5, CXCL10, and CXCL11. Discussion Complement depletion represents a promising mode of immunotherapy in cancer by its ability to impair tumor growth by increasing the host’s effective immune response to tumor and diminishing the immunosuppressive effect created by the tumor microenvironment and ultimately could be utilized as a component of combination immunotherapy.

The Complement C3a Receptor Contributes to Melanoma Tumorigenesis by Inhibiting Neutrophil and CD4+ T Cell Responses

“…In accord with the recent study by Downs-Canner et al (27), we also showed upregulation of the CCR5 ligand, CCL5 (RANTES) at the protein level, along with a slight, but not significant, increase in the Th2 cytokine IL-10. Increased CCL5 levels have been associated with unfavorable outcomes in some cancers (35), but they predict survival in others (36), regulating antitumor immunity (37) and synergizing with CXCR3 ligands to attract effector T cells into cutaneous metastases and inhibit tumor growth (38).…”

“…The canonical proinflammatory mediator C5a has been widely implicated for a role in tumor growth, with both tumor-promoting and tumor-inhibitory effects reported, depending on tumor type, immune status of the host, and C5a levels (6)(7)(8)(9)26). Although these and other studies (27) have shown that tumor growth is reduced in the absence of C3 (which generates both C3a and C5a), the tumor-promoting effects have been attributed solely to C5a. Until now, there have been no studies investigating the role of the upstream activation fragment C3a in tumor growth.…”

High-Fat Diet-Induced Complement Activation Mediates Intestinal Inflammation and Neoplasia, Independent of Obesity

“…Recent findings indicate that complement activation in the tumor microenvironment leads to tumor growth and metastasis. In vivo models using breast, lung and colon cancer cell lines showed that C5aR-mediated signaling creates a microenvironment that promotes growth through recruitment of myeloid-derived suppressor cells (MDSCs) and inhibition of anti-tumor immune responses mediated by CD8 + and CD4 + T cells (25, 27–29, 36). In addition, C5a-induced inflammation is associated with promotion of angiogenesis and tumor progression.…”

C5aR1 regulates migration of suppressive myeloid cells required for costimulatory blockade-induced murine allograft survival

“…The observations that C5aR1 is required for Mreg migration/accumulation into tumors and into transplants and, as a consequence, to mediate tumor and transplant survival illustrate commonality of mechanism despite distinct pathophysiologic contexts. Complement component C3 has been separately shown to be important in the differentiation of MDSCs, an effect that has not been attributed to C5aR1. While we have not formally documented the source of C5a in this system, we speculate, based on our previous work, that it derives from recipient plasma and/or recipient immune cell–produced complement …”